This application is a 371 of PCT/JP 99/00285 filed Jan. 22, 1999.
1. Technical Field
The present invention relates to a sugar-coated tablet formed by coating a core tablet using a mixture of lactulose and raffinose having various physiological effects as the sugar coating base.
In this specification, the core tablet refers to a tablet that is produced by the tabletizing of a composition that exhibits pharmacological action, and the sugar coating base refers to a composition that is used to coat the core tablet.
2. Background Art
Currently, coatings for medicinal preparations are frequently used in order to mask the flavor or odor of a drug, ensure the safety of the druggist by preventing the generation of drug dust, improve the stability of the drug by protecting the drug from light, water and oxygen, and improve the efficacy or stability of the drug by imparting solubility in intestines or controlled release effects. In addition, known methods for coating medicinal preparations involve gelatin coating, dry coating, sugar coating, film coating and powder coating, but gelatin coating and dry coating are almost never used for the sole purpose of coating, whereas powder coating has been the subject of much investigation and is considered to be a future technology. Consequently, sugar coating and film coating are currently the main methods.
Conventional sugar coating bases have been aqueous solutions of sugar (syrups), and it is said that tablets with excellent hermetic properties and smooth surface are obtained by the formation of tight block-form structures of sugar crystal. Calcium lactate is also known, in addition to sugar, as a sugar coating base, and other known substances include talc used as a sugar coating dispersion agent, precipitated calcium carbonate used as a sugar coating suspension agent, gelatin, gum arabic and pullulan used as sugar coating binders, and carnauba wax used as a sugar coating glossing agent (Hisashi Ichibangase, Kaneto Uekama, and Yuki Odagiri, Eds.xe2x80x9cDrug Product Development [Iyakuhin no Kaihatsu] Vol. 12, Preparation Materials [Seizai Sozail] Ixe2x80x9d Hirokawa Shoten, Heisei 2 Nen/1990).
In addition, the use of sugar alcohols as materials for coating foodstuffs has been disclosed (Japanese Laid-Open Patent Publication No. H9-313109, 1997), and the use of fine granulated sugar and corn starch as materials for coating compound-grain granules soluble in intestines has been disclosed (Japanese Laid-Open Patent Publication No. H5-186337, 1993).
On the other hand, lactulose is a type of disaccharide composed of galactose and fructose (4-O-xcex2-D-galactopyranosyl-xcex1-D-fructose), and is manufactured by subjecting lactose to the Lobry de Bruyn transformation. Lactulose is known to be a Bifidobacteria stimulating factor (Diagnosis and New Drugs [Shindan to Shinyaku], Vol. 10(5), p.75 (1973)). The substance is used in prepared powdered milk and powdered milk for weaning. In addition, lactulose is known to have the action of mitigating diseases such as hepatic encephaly and hepatic coma, and the substance has previously been used for treating these patients (Psychiatric Medicine [Seishin Igaku], Vol. 15(10), 1101 (1973)). However, when lactulose is used by itself as a sugar coating base, its high viscosity makes it impossible to uniformly coat the core tablet.
Raffinose is a type of trisaccharide that is composed of D-glucose and D-fructose, and is manufactured from a beet syrup by isolating with chromatography. Raffinose has already received a general evaluation as a foodstuff material for special health needs by the Japan Health and Nutrition Foodstuff Society [Nihon Kenkou. Eiyou Shokuhin Kyoukail]. A method for manufacturing sugar coatings has also been disclosed in which a sucrose syrup containing raffinose at an extremely low concentration of 2% (wt %, likewise below when not otherwise specified) or less is used for coating (Japanese Patent Publication No. S58-50968(1983)).
However, as is clear from the prior art described above, sugar-coated tablets produced using a sugar coating base which contains, as its effective component, a mixture in which at least an equivalent amount of raffinose is mixed with lactulose having various physiological actions are unknown, and are absent from the literature.
The present invention provides a sugar-coated tablet that employs, as the sugar coating base, a mixture composed of raffinose and lactulose having various physiological effects, which does not employ any sucrose, and has anticariogenic properties.
The present invention relates to a sugar-coated tablet formed by coating a core tablet with a sugar coating base that contains, as its effective component, a mixture of lactulose and raffinose.
The present invention provides a sugar-coated tablet that does not stick to the oral cavity when taken, has no unpleasant texture when ingested, a good sensation (mouthfeel) and excellent taste.
With the foregoing in view, the inventors began with the use of lactulose having various physiological effects as a sugar coating base, attempting to manufacture a sugar-coated tablet using a sugar coating base composed of lactulose alone, and mixtures of lactulose and sucrose, oligosaccharides, sugar alcohols and other sugars. However, adequate product quality could not be obtained in the form of a sugar-coated tablet because it was not possible to uniformly coat the core tablet due to excessive viscosity.
The inventors thus carried out painstaking investigations towards a solution to these problems, and arrived at the present invention upon discovering that when at least one part (by weight) of raffinose is mixed with respect to 1 part (by weight) of lactulose for use as the sugar coating base, the viscosity of the mixed aqueous solution can be greatly reduced, making it possible to provide a sugar-coated tablet with a uniformly coated core tablet.
It is an object of the invention to provide a sugar-coated tablet formed using a sugar coating base that is a mixture of raffinose and lactulose having various physiological effects, containing no sucrose, which is primarily used in conventional sugar coating bases, which has anticariogenic properties result from the use of lactulose and raffinose.
A solution to the above problems provided by the present invention is a sugar-coated tablet formed by coating a core tablet with a sugar coating base that contains a mixture of lactulose and raffinose as its effective component.
The present invention, in a preferred aspect, contains a mixture containing a ratio of at least 1 part (by weight, likewise below when not otherwise specified) of raffinose with respect to 1 part (by weight) of lactulose.
In another preferred aspect, the core tablet contains, as its effective component, one or both of (a) and (b) below:
(a) cell powder of one or more selected from the group consisting of microorganisms of the genus Bifidobacterium, microorganisms of the genus Lactobacillus, microorganisms of the genus Streptococcus, microorganisms of the genus Pediococcus and microorganisms of the genus Leuconostoc (these microorganisms are all referred to below as xe2x80x9clactic acid bacteriaxe2x80x9d), and
(b) one or more selected from the group consisting of lactoferrin, peptide and lactulose.
The present invention is described below.
The lactulose and raffinose used in the sugar coating base of the present invention are commercially-available products, and can be manufactured by well-known methods. For example, lactulose can be manufactured as follows based on the methods disclosed in Japanese Laid-Open Patent Publication No. H3-169888 (1991) and Japanese Laid-Open Patent Publication No. H6-228179 (1994). Sodium hydroxide is added to a 10 wt % aqueous solution of commercial lactose, and said mixture is heated for 30 min at a temperature of 70xc2x0 C., and cooled. Subsequently, the cooled solution is purified with an ion exchange resin, concentrated, and cooled to bring about crystallization. The unreacted lactose is then removed to obtain a lactulose aqueous solution with a solids content of about 68% (lactulose is contained in the solids content at about 79%). This aqueous solution is then passed through a strong acid ion exchange column to remove the component containing lactulose, whereupon the substance is concentrated to obtain a purified lactulose aqueous solution with a solids content of about 68% (lactulose is contained in the solids content at about 86%). This method is described in Japanese Laid-Open Patent Publication H3-169888 (1991).
In addition, the lactulose aqueous solution (syrup) obtained by the method described above is concentrated to a solids content of about 72%, this concentrated solution is cooled to 15xc2x0 C., lactulose trihydrate crystal is added as seed crystal, and the solution is gradually cooled as necessary to 5xc2x0 C. over 7 days while stirring to generate crystals. After 10 days, the solid content of the supernatant is reduced to about 61%, and crystals are separated with a filter cloth centrifuge from the solution containing the crystals. The crystals are washed in cold water at 5xc2x0 C., and are dried to obtain lactulose crystals with a purity of 95% or greater (Japanese Laid-Open Patent Publication H6-228179 (1994)). The lactulose that is used in the present invention is preferably as high a purity as possible, with material having a purity of 95% or greater being particularly-preferred.
The raffinose used in the sugar coating base of the present invention is a commercially-available product, which commercially available product is generally manufactured from beet syrup by the method described below. Beet syrup is subjected to chromatography in order to remove the fraction containing the raffinose, which is then concentrated and crudely crystallized. The crude crystals are then dissolved, filtered, and purified to collect crystals that are then dried to obtain the purified crystal product (Technology for the Effective Use of New Foodstuff Materials [Shokuhin Shinsozai Yuukou Riyou Gijutsu] Series No. 6 xe2x80x9cRaffinosexe2x80x9d, p.2, Incorporated Confectionery General Technology Center (Shadanhoujin Kashi Sougou Gijutsu Senta, 1996).
In the present invention, a sugar coating base is used that has, as its effective component, a mixture of at least one part of raffinose, and preferably 1.5-10 parts, with respect to one part of lactulose manufactured as described above.
The core tablet of the sugar-coated tablet of the present invention can be any core tablet containing various types of well-known effective components for drug tablets, and is a material that is produced by tabletizing a drug composition that exhibits various effects.
Particularly desirable core tablets used in the sugar-coated tablet of the present invention are materials that contain lactic acid bacteria biomass powder. This lactic acid bacteria biomass powder can be live biomass powder or dead biomass powder, but live bacteria powders are preferred because they have intestinal regulating actions. The biomass powder of the lactic acid bacteria can be a commercially-available product, or can be prepared by well-known methods (for example, Japanese Laid-Open Patent Publication No. H1-221319 (1989). However, an example is presented below.
A seed culture of one or more types of microorganism selected from the group consisting of microorganisms of the genus Bifidobacterium, microorganisms of the genus Lactobacillus, microorganisms of the genus Streptococcus, microorganisms of the genus Pediococcus and microorganisms of the genus Leuconostoc is bulk cultured by a common method, and various sugars, amino acids, starches, gelatin, nonfat dry milk or other dispersion media having protective action are added as necessary to the bacteria that are separated from the culture solution. The material is then freeze-dried to prepare a dry biomass. A more detailed preparation method for biomass powders of lactic acid bacteria is found in Reference Examples 1 to 4 below.
The lactulose that is used in the core tablet is the same as the material used for the above sugar coating base.
Also, the lactoferrin that is used in the core tablet is a commercially-available product or a substance that is manufactured by a well-known method, for example, the method disclosed in Japanese Patent Publication No. H6-13560 (1994), and can be manufactured as described below.
CM-Sephadex C-50 (made by Pharmacia) with a volume expansion of 3.0 and a hemoglobin adsorption capacity of 3.9 g/100 mL having carboxymethyl ion exchange groups is swelled in water and used as an Na-type ion exchanger. This material is introduced into raw nonfat milk, and is stirred for 16 h at 4xc2x0 C. in order to bring about contact therewith, the ion exchanger is removed, and is loaded into a column. Water is then passed through the column to remove the nonfat milk content that has attached to the ion exchanger. 1.6% sodium chloride solution is then passed through the column and the first fraction adsorbed to the ion exchanger (proteins other than lactoferrin) is released and removed. Subsequently, 5% sodium chloride solution is passed through the column, and the liquid is recovered. Sodium chloride is then removed from the recovered liquid using an ultrafiltration film (made by DDS) with a differential molecular weight of 20,000, and the resulting concentrated liquid is freeze dried to obtain lactoferrin at a purity of 98% or greater.
The peptide that is used in the core tablet is a commercially-available product or a hydrolysis product of food protein manufactured by well-known methods. Examples are peptides obtained by the enzymatic hydrolysis of casein or whey protein (Japanese Patent Publication No. S54-36235 (1979), Japanese Laid-Open Patent Publication No. H7-303455 (1995), Japanese Laid-Open Patent Publication No. H8-112063 (1996) and Japanese Laid-Open Patent Publication No. H8-2286692 (1996). By varying the hydrolysis ratio, peptides that are appropriately modified in terms of molecular weight distribution can be obtained.
The lactoferrin, peptide and lactulose can be used individually or in any combination in the core tablet of the sugar-coated tablet of the present invention. For example, a mixture can be used that is produced by mixing 0.5 part of peptide and 2 parts of lactulose with respect to 1 part of lactoferrin.
In addition, any combination of the aforementioned lactoferrin, peptide and lactulose as well as the aforementioned lactic acid bacteria biomass can be used in the core tablet of the sugar-coated tablet of the present invention.
In addition, other well-known components that are used in drug manufacture can be used as other components in the core tablet of the sugar-coated tablet of the present invention, examples of which include sucrose fatty acid esters, glycerin fatty acid esters and other lubricants, sugars, sweeteners, fragrances, thickeners, and emulsifiers for improving flavor and taste, which may be added in allowed amounts to prepare the raw material for the core tablet. In addition, examples of sugar-coating elements that can be used include well-known shellacs and other water repelling agents, talc, powdered glucose and other dispersants or suspension agents, gum arabic, gelatin and other binders, and colorants, carnauba wax, beeswax and other glossing agents (Hisashi Ichibankase, Kaneto Uekama, and Yuki Odagiri, Eds. xe2x80x9cDrug Development [Iyakuhin no Kaihatsu] Vol. 12, Preparation Materials Ixe2x80x9d p.205, Hirokawa Shoten (1990)).
In the sugar-coated tablet of the present invention, the raw material for the aforementioned core tablet can be milled by means of known milling devices (for example, a rotating pin mill (made by Hosokawa Micron, etc.). Alternatively, the material can be granulated, prior to tabletizing, using a well-known granulator such as an extrusion granulator (for example, the EKUSTURUUDO O MIKKUSU (made by Hosokawa Micron)), or a fluid bed granulator (for example a GURADDO fluidized granulator drier (Okawara Seisakusho)), followed by tabletizing. However, glaze, fragrance and the aforementioned live biomass of the lactic acid bacteria are preferably not granulated.
With the sugar-coated tablet of the present invention, the core tablet is manufactured by using a well known method or device to tabletize the raw material for the core tablet that has been prepared as described above. The device used for tabletizing is a granule compression-type tabletizer, and although any device such as a well-known rotary tabletizer, eccentric tabletizer, etc., can be used, it is preferable to use a rotary tabletizer from the standpoint of productivity on an industrial scale. Specifically, for example, the raw material for the core tablet prepared as described above is supplied to a rotary tabletizer (for example, the HT-PA compact high-speed tabletizer (made by Hata Tekkosho) and the material is compressed between upper and lower molds that provide the shape of the desired tablet, thus forming tablets. The compression force during tabletizing varies depending on the composition of the tablet raw material, the tablet shape, the tabletizing rate and the type of tabletizer, but is normally in the range of 1 to 5 tons. Preliminary compression at a pressure of about 1 ton can also be carried out with the tablet raw material immediately prior to the primary tabletization step.
When the shape of the sugar-coated tablet of the present invention is very unusual, the strength is greatly decreased. In general, however, tabletizing can be carried out using any general tablet shape, such as circular, triangular, square, football-shaped, buckle-shaped, flower-shaped and hat-shaped.
The sugar-coated tablet of the present invention can be manufactured by the well-known pan coating method (for example, using a rotary sugar coating pan (made by Fuji Yakuhin Kikai), etc.) or by a coating method involving a fluidized bed device. Pan coating involves inserting and rotating the core tablets in a pan, while the coating solution is added or sprayed onto the fluid tablet surface by means of a manual operation or automated operation. Dispersant is introduced as necessary, and hot air is directed at the surface of the tablets through a ventilation duct from the front surface of the pan. The solvent is thereby removed and the tablets are dried, which process is repeated any desired number of times to manufacture the sugar-coated tablets (Yoshinobu Nakai, Ed. Drug Development [Iyakuin Kaihatsu] 11, xe2x80x9cUnit Processes and Devices for Preparationsxe2x80x9d [Seizai no Tanisousa to Kikai], p.94, Hirokawa Shoten, 1989). A more detailed description follows.
In manufacturing the sugar-coated tablet of the present invention, a large increase in viscosity at the surface of the tablets is not seen although the tablets that are flowing through the pan assume a wetted state due to the introduction of sugar coating liquid, and each and every tablet exhibits an appropriate fluid condition. As a result, the tablets come into contact with the sugar coating liquid nearly uniformly, so that addition of the sugar coating liquid can be performed by an introduction method or spray method. The shape of the layer and the drying rate at this time depend on the rotation rate of the individual tablets, and thus baffles or floats can be arranged in the pan in order to aid in rotation. The composition ratio of the lactulose and raffinose mixture and the additives (talc, calcium carbonate, calcium phosphate, calcium sulfate, colorant, etc.) in each layer of the sugar coating is 1:0.5 to 2.0 for the sub-coating layer, and 1:0.5-1.2 for the smoothing layer. In the coloring layer, only a mixture of lactulose and raffinose is used, so that the mixing ratio of lactulose and raffinose increases towards the outer layer. Examples of binders that can be added to the sugar coating liquid in order to bind the layers include, in addition to gelatin and gum arabic which have long been used, polyvinyl pyrrolidone or pullulan which is a type of polysaccharide. However, addition of gum arabic is restricted to the subcoating and smoothing layers, where as other binders are used in all of the layers in decreasing concentrations towards the outer layer. Dyes used for coloration are added primarily for coloring.
In finishing the product, a thin finishing layer composed of a mixture of lactulose and raffinose can be formed on the surface to create gloss, and carnauba wax, beeswax and other substances can be used thereon for polishing.
In order also to improve the drying efficiency during coating, a ventilated drying coating device wherein heated air is continually passed through the interior of the rotary mixing bed can be used for manufacturing the sugar-coated tablet of the present invention (for example, a rotary type coater (made by Furointo Sangyo)). With this device, the cylindrical pan has a double-layer structure, with punch holes provided on the inner side. Because the pan causes dry air to flow in the spaces between the tablets that constitute a rotating mixing bed, the drying efficiency is increased at about 1.5-2 times with respect to ordinary pans. Also, a reverse-format device wherein the dry air is made to flow from the outside rather than the inside can also be used for manufacturing the sugar-coated tablet of the present invention.
The sugar-coated tablet of the present invention manufactured as described above makes it possible to uniformly apply a sugar coating base onto a core tablet by means of mixing prescribed amounts of raffinose, in spite of the fact that it is difficult to coat lactulose alone on core tablets. A product is thus obtained that has good external appearance as well as excellent physiological effects and taste (mouthfeel) not attainable with conventional products.